The proposed research will test the hypothesis that differences in the number or affinity of receptors which bind nicotine account for differences in initial sensitivity or tolerance to nicotine. Our animal models will be inbred strains of mice, and appropriate hybrids and backcrosses, which differ in initial sensitivity or tolerance development. The research will also assess the interactions of nicotine with miscarinic and Alpha-bungarotoxin receptors. Susceptibility to nicotine's effects (acute sensitivity or tolerance) will be quantified using a number of tests, and receptor number and affinity will be measured in several brain regions and tissues (adrenal gland, skeletal muscle, spinal ganglia) in order to investigate the possibility of correlations between tolerance development and receptor alterations. Because one of the strains we propose to study does not develop tolerance to nicotine, it will provide an ideal control for assessing the role of receptor changes in tolerance development. Since genetic factors apparently influence human smoking behavior, the proposed studies should provide data which will be useful in determining whether nicotine plans a role in this genetic effect. The neurochemical studies should be of value in determining whether receptor differences underlie genetic differences in human smoking behavior.